Development and Translation of NanoBEO, a Nanotechnology-Based Delivery System of Bergamot Essential Oil Deprived of Furocumarins, in the Control of Agitation in Severe Dementia

Abstract

Dementia is one of the most common causes of disability worldwide characterized by memory loss, cognitive impairment, and behavioral and psychological symptoms (BPSD), including agitation. Treatment of the latter consists of the off-label use of harmful atypical antipsychotics, though a significant reduction is afforded by pain control. The use of an essential oil endowed with analgesic properties and devoid of toxicity would represent an important option for the management of agitation in dementia. Therefore, the aim of this study was to engineer a nanotechnology delivery system based on solid lipid nanoparticles loaded with bergamot essential oil (BEO) and devised in the pharmaceutical form of an odorless cream (NanoBEO) to confirm its analgesic efficacy for further development and application to control agitation in dementia. BEO has proven strong antinociceptive and anti-allodynic properties and, in its bergapten-free form, it is completely devoid of phototoxicity. NanoBEO has been studied in vivo confirming the previously reported analgesic activity of BEO to which is now added its anti-itching properties. Due to the nanotechnology delivery system, the stability of titrated BEO components is guaranteed. Finally, the latter invention, currently under patent consideration, is smell-devoid allowing efficacy and safety to be established in double-blind clinical trials; until now the latter studies have been impeded in aromatherapy by the strong odor of essential oils. A clinical trial NCT04321889 has been designed to provide information about the efficacy and safety of NanoBEO on agitation and pain in patients suffering from severe dementia.

Keywords: BPSD; agitation; dementia; essential oil of bergamot; nanotechnology delivery system; pain.

Figure 1

Photomicrograph of solid lipid nanoparticles (SNL) with α-tocopheryl stearate (α-TFS-SLN) visualized by transmission electronic microscopy (TEM).

Figure 2

Antinociceptive effect of topical application of NanoBEO (1 mg/mouse) on capsaicin-induced licking/biting behavior. The duration of licking/biting induced by capsaicin has been determined using the 5-min period starting immediately after the injection of capsaicin. Empty cream (1 mg/mouse) has been used as a control and this has failed to affect the capsaicin-induced nociceptive response. Values are expressed as mean ± SEM (n = 8). Values of p < 0.05 have been considered statistically significant. Improvement over control of 59.26%, ** p < 0.01.

Figure 3

Antinociceptive effect of the topical application of NanoBEO (1 mg/mouse) on the 0.5% formalin test. The nociceptive behavior induced by formalin has been scored as the amount of time spent licking and biting the injected paw. Empty cream (1 mg/mouse) has been used as a control and this has failed to affect the formalin-induced nociceptive response. Values are expressed as mean ± SEM (n = 8). Values of p < 0.05 have been considered statistically significant. Improvement over control of 59.78%, ** p < 0.01.

Figure 4

Antiallodynic effect of topical application of NanoBEO (1 mg/mouse) on partial sciatic nerve ligation (PSNL). Empty cream (1 mg/mouse) has been used as a control and this has failed to affect PSNL-induced mechanical allodynia. Each value represents mean ± SEM (n = 10). Values of p < 0.05 have been considered statistically significant. Improvement over control of 58.76%, ** p < 0.01.

Figure 5

Anti-scratching effect of intradermal (i.d.) administration of NanoBEO on 4-methyl-histamine-induced behavior. The NanoBEO (1 mg/mouse) was used as pretreatment (30 min) (a) or immediately after (b) and has resulted as effective on the scratching behavior under both circumstances. The scratching time has been scored as seconds per 30 min. Empty cream (1 mg/mouse) has been used as a control and this has failed to affect itching. Values are expressed as mean ± SEM (n = 8). Values of p < 0.05 have been considered statistically significant. (a) Improvement over control of 53.13%, *** p < 0.001; (b) improvement over control of 56.67%, *** p < 0.001.